Method of sedation

ABSTRACT

THE SPECIFICATION DISCLOSES THE USE OF 3,5-DIMETHYL-5-HYDROXY-2,4-DICARBETHOXYCYCLOHEXANONE AS A SEDATIVE-HYPNOTIC.

United States Patent 3,718,745 METHOD OF SEDATION Koji Nakanishi, New York, and Jonas A. Gylys, Manilius, N.Y.; said Gylys assignor to Bristol-Myers Company, New York, N.'Y. No Drawing. Filed Feb. 9, 1972, Ser. No. 224,970 Int. Cl. A61k 27/00 US. Cl. 424--311 2 Claims ABSTRACT OF THE DISCLOSURE The specification discloses the use of 3,5-dimethyl-5-hydr.0Xy-2,4-dicarbethoxycyclohexanone as a sedative-hypnotic.

BACKGROUND OF THE INVENTION Sedatives and hypnotics are drugs which are useful in therapy for the purpose of inducing a state of calmness or sleep. Sleep is considered to be, at least partially, a conditioned reflex which like appetite rises, often to acute levels, and then wanes. Sleep disturbances, although often associated with some form of pain or physical discomfort are often the result of anxieties and other psychic circumstances. Drugs which allay anxiety and apprehension and, therefore, induce or maintain sleep are among the more useful medicaments in general use. Unfortunately, many such drugs are characterized by untoward side effects such as respiratory and circulatory depression at use-dose levels. Moreover, certain sedatives are subject to various disadvantages due to the development of physical or phychological dependence.

It is an object of this invention to provide a method for the treatment of sleep disturbances. Another object of the invention is to provide medicaments for inducing calm and sedated states with minimal side effects, particularly with respect to depression of the central nervous system and the cardiovascular system. Other aspects of the invention are directed to means for the potentiation of sleep maintaining drugs and minimization of withdrawal symptoms usually associated with barbiturate dependance.

This invention is directed to the compound 3,5-dimethyl-5-hydroxy-2,4-dicarbethoxycyclohexanone and particularly to the use of this .compound as a therapeutic or medicinal agent having useful effects on the central nervous system of mammals, including man, and also to therapeutic compositions containing the compound in a form suitable for oral and parenteral administration.

The compound 3,5-dimethyl-5-hydroxy-2,4--dicarbethoxycyclohexanone has been found to have a valuable phar; macological profile with respect to other known CNS agents. In general, this compound has properties which make it useful as a CNS-depressant and, more specifically, as a medicinal agent in the treatment of sleep distur bances. This compound can be classified as a sedative-hypnotic and has particular activity as a sleep-inducing drug rather than for the maintenance of sleep. The rapid onset and relatively short duration of effect which characterize this compound as compared to other sedative agents are properties which make it particularly suitable for use as a hypnotic. Notable among the properties which characterize this compound and also distinguish it from barbiturates is the absence of respiratory depression at effective doses.

The general CNS profile of 3,S-dimethyl-5-hydroxy-2,4- dicarboethoxycyclohexane, hereafter referred to as NN- 51, as compared to certain referenceCNS depressants, is summarized in Table I, below.

TABLE I CNS Depressant Activity and Acute Toxicity of 'NN 51, G-lutethimlde Chloral Hydrate and Pentobarbital Na in the Mouse and Rat Effective dose, mg./kg., po

1 Results from fasted rats, all other values were obtained in fed rats or m ce.

Based on the data in the above table, certain patterns of CNS activity are evident. CNS depression, based on reduced motor activity and muscle relaxation, is seen in rats at doses widely separated from those causing hypnosis based on loss of righting reflex (HD or motor incoordination and muscle weakness (PD as compared to the reference compounds. Similarly, a wide separation between the hypnotic dose (HD and the lethal dose (LD is shown. The wide separation between effective dose and lethal dose indicates a shallow dose-response curve.

It was also found that NN-SI had a rapid onset in laboratory animals, in some cases, being less than about 15 minutes vw'th peak effects being obtained in about 60 minutes. Duration of action was dose-dependent and found to be brief in comparison to the reference compounds. I Y

The above factors when combined with the absence of respiratory depression make this compound of substantial interest for use as a sedative. When administered in an effective amount, it is conducive :to a state of calm or sleep. Depending on the degree of sedation desired, effective doses can range from about 25 mg. to about 1 gm. per kg. of body weight per day. A preferred range for sedative effect is fromabout 25 to about 300 mg. per kg. of body weight per day.

NN-Sl was found to potentiate hexobarbital and ethanol depression, as measured by an increase in sleeping time. In these tests, doubling of the sleeping time, as compared to control animals, was considered a significant drug effect. Effective doses in mg. per kg. for NN5l, glutethimide, chloral hydrate and sodium pentobarbital administered one hour before hexobarbital were respectively 25, 35, 7300 and 50.

NN-l was also found to be effective as an antagonist for the stimulant action of phenylenetetrazol.

NN-Sl has been found to have an effect on the withdrawal symptoms usually associated with barbiturate d pendence. Tests in both dogs and rats indicate that NN-51 antagonizes barbital withdrawal symptoms wihtout intensification of the withdrawal signs when administration of NN-Sl is stopped. In a series of tests on dogs, substitution of the compound for sodium barbital at a dose level of 300 mg./kg. allowed for gradual withdrawal of sodium barbital without appearance of major abstinence symptoms, i.e., convulsions and delirium, upon termination of treatment.

Table II, below, summarizes data showing further aspects of CNS activity. The test procedures are described below.

ialvcd 170 300 170 50 Rotarod.--Drug effects upon motor coordination were determined using a Rotarod apparatus (Kinnard & Carr, 1957). Male mice (Taconic) were trained to stay on a rod rotating at 16 r.p.m. for 60 seconds. Groups of five mice were tested 05, 1, 3 and 6 hours after drug administration and the mean time the mice stayed on the rod was determined for each test period. A time limit of 60 seconds for staying on the rod was used so that fatigue would not contribute to the outcome of the results. A 50 percent reduction of time on the rod as compared to control groups run concurrently was considered a significant drug effect.

Spontaneous motor activity-Spontaneous locomotor activity was determined in circular, photocell activity cages manufactured by Woodard Research Corp. Groups of three male mice (Taconic) were used and tests of 20 minutes duration were carried out 0.5, l, 3 and 6 hours after drug administration. A 50 percent reduction in counts during each observation period as compared to a concurrently run control group was considered a significant drug effect.

Tables III and IV, below, summarize some observations of gross behavioral effects of the compound in laboratory animals.

TABLE III Gross Behavioral Effects of NN-51 in the Cat Dose, Form of mg./kg. administration Observations N N 5l;

50, po... Capsule Minimal sedation.

Dose response not evident at dose range of 100-400 mg./kg.; onset 30 minutes; sleep but readily aroused upon stimulation; no ataxia or reflex impairment; cmesis at 400 mg./ kg.; duration -240 min.

200,po.. Suspension Onset-20 minutes; sleep with easy arousal; mild ataxia; no reflex impairment; duration -l80 minutes.

400, po do Onset10 minutes; marked ataxia and loss of righting reflex (30 minutes) with return at 120 minutes; rigid extension of forelimbs, increased respiratory rate and vocalization linked winth respiratory movements (25 to 45 minutes); muscle relaxation with mild ataxia until recovery (-i80 minutes); duration-recovery overnight. 25,.ip, Solution... Minimal sedation.

TABLE IIICoutinued Dose, Form of mg./kg. administration Observations 100, ip do Onset-l0 minutes; loss of righting reflex with rigid forelimb extension (20 minutes) and recovery at 40 minutes; marked ataxia minutes: duration -3tl0 minutes with complete recovery.

TABLE IV Gross Behavioral Effects of NN-5l, in the Dog Dose Form of mgJkg. administration Observations 100, po Capsule No significant efiect.

250, p0 do Onset 30 minutes; sleep 30 to 60 minutes; duration -30 minutes; minimal effects.

500,po do Onset 30 minutes; sleep (120 minutes) most obvious at 60 minutes; duration -l20 minutes.

100, po Suspension Onset 15 minutes; sleep -120 minutes; duration-l20 minutes.

200, p0 do Same as 100 mgJkg. p0; cmesis l/2 dogs.

400,po ..do Onset 10 minutes; emcsis, marked ataxia; loss of righting reflex-30 minutes (2/4 dogs); sleep and ataxia lasting minutes; duration-180 minutes.

1,000, po do Onset 5 minutes; cmesis, limb rigidity fast respiration, vocalization linked with respiratory movements, loss of righting reflex (-l20 minutes), appeared unconscious; secondary muscle relazxation (-360 minutes); duration 360 minutes with recovery overnight. 20, iv... Solution Minimal and brief ataxia (2 minutes) 40, iv ..do Marked ataxia and CNS depression withigraduai recovery in 60 minutes. 60, iv .do Loss of righting reflex (20 minutes) with limb rigidity and fast respiration (10 minutes); followed by ataxia (20 minutes); duration -l50 minutes.

100, iv .do Loss of righting reflex (60t080 minutes) with limb rigidity and fast respiration (35 minutes); followed by marked ataxia60 minutes; duration overnight recovery.

Cardiovascular safety was evaluated and the data revealed that the compound did not have any significant effect in the anesthetized dog on arterial blood pressure, central venous pressure, pulse pressure, cardiac rate and EEG at iv doses through 20 mg./kg. There were some indications by acute biphasic blood pressure changes, increased central venous pressure and irregularities in cardiac rhythm at 50 and 100 mg./ kg. These changes wer reversible in nature in the anesthetized dog. There were no acute deaths even after intravenous administration Of cumulative doses as high as 184 mg./kg. In view of the fact that CNS depression is not a predominant feature of this compound, the cardiovascular effects appear to be independent of CNS action. Studies in the conscious dog revealed NN-Sl to be safe cardiovascularly at the highest doses tested (60 mg./kg. iv and 200 mg./kg. p0).

The preparation of 3,S-dimethyl-S-hydroxy-2,4-dicarboethoxycyclohexanone is described by Horning et al. in the Journal of Organic Chemistry, 9, 548 (1944). In general, a mixture of ethyl acetoacetate and acetaldehyde is maintained in the presence of piperidine until a crystalline mass is obtained. The crude product is collected by filtration and recrystallized from a mixture of ethanol and water to give a pure product in good yields.

The compound 3,5 dimethyl 5 hydroxy-2,4-dicarboethoxycyclohexanone can be administered to a living animal body, including man, in the form of pharmaceutical preparations containing the compound in conjunction or admixture with pharmaceutical carriers, excipients and the like. The pharmaceutical preparation can be solid or liquid suitable for oral, parenteral or rectal administration. Suitable forms for administration include tablets, powders,

capsules, solutions, emulsions, suspensions and suppositories. The dose may vary from about 50 to about 200 mg. per day per subject, depending on the weight of the subject and the nature and intensity of drug effect desired.

What is claimed is:

1. The method of inducing sedation which comprises administering a sedation-inducing dose of 3,5-dimethyl- S-hydroxy-2,4-dicarboethoxycyclohexanone.

2. The method of claim 1, wherein the compound is administered orally in amount-s of between 50 and 200 mg. per day.

References Cited Journ. Org. Chem., vol. 9, pp. 547-550 (1944).

STANLEY J. FRIEDMAN, Primary Examiner 

